In spite of the recent remarkable progress of medical technology, various adult diseases, such as malignant tumors, arteriosclerosis and articular rheumatism, have become serious social problems. Diabetes, among others, is a disease causing a number of severe angiopathies such as cerebrovascular disorders and ischemic heart diseases and the number of patients with latent diabetes is especially large.
According to a broad classification made by the World Health Organization (WHO), diabetes includes type I diabetes mellitus (insulin-dependent diabetes; IDDM) caused by an absolute deficiency in insulin and type II diabetes mellitus (non-insulin-dependent diabetes; NIDDM) resulting from a relative deficiency in insulin. As main chronic complications, there may be mentioned neuropathy, retinopathy and nephropathy, among others, and, in all of these diseases, hyperglycemia is the principal causative factor. In particular, diabetic nephropathy, at an advanced stage, results in renal failure, for which dialysis therapy is necessary, and the five year survival rate after the start of dialysis is about 50%, which is very low as compared with that in non-diabetics, and patients with diabetic nephropathy still have a poor prognosis. Meanwhile, in 1998, the yearly number of patients newly submitted to dialysis therapy ranked above that of patients with chronic glomerulonephritis and, thus, diabetic nephropathy occupied the first place among causative diseases; that number has been increasing year after year (Non-Patent Document 1).
Type II diabetes is considered to be induced by a relative decrease in insulin secretion, together with an increase in insulin resistance as resulting from obesity, overeating, lack of exercise, stress and like other environmental factors. It is known that this insulin resistance is widely involved not only in diabetes but also in the onset and progress of some other disease such as arteriosclerosis and, as for the main cause thereof, it is known that a certain abnormality is seen in each stage of glucose metabolism.
The insulin receptor selectively binding to insulin and playing a role in the uptake of glucose into the cell in glucose metabolism is a tetramer glycoprotein composed of two α subunits having a molecular weight of about 135,000 and two β-subunits having a molecular weight of about 95,000 as coupled together by S—S bonding and occurring in the cell membrane of most cells in the body. Since the 1970's, a large number of studies have been made about the structure and other features thereof (Non-Patent Document 2).
On the other hand, it has been reported that a physiologically active substance like the insulin receptor on the cell occurs in body fluids. That substance is considered to be the complete or partly deficient insulin receptor or the like (soluble insulin receptor) excessively expressed in body fluids from some or other cause and it is known that this causes hyperinsulinemia or causes increased glucose production in the liver to bring about a hyperglycemic condition (Non-Patent Document 3). Patent Document 1 discloses a method of removing insulin-binding proteins but does not disclose any specific peptide.
When such a soluble insulin receptor as mentioned above is present in body fluids, it binds to insulin in the body fluid and thus inhibits the insulin activity, possibly causing insulin resistance.
There is no effective method of treatment found as yet against IBPs, including this soluble insulin receptor and the like, although there are several types of insulin resistance lowering agents.
Also there are several peptides having insulin activity and used as drugs but any peptide incapable of binding to other proteins (albumin etc.) in contact with body fluids, namely improved in selectivity, has not been found out as yet.
Patent Document 1: WO 02/094344
Non-Patent Document 1: Toseki Kaishi (Journal of the Japanese Society for Dialysis Therapy) 37 (1) (2004) 1-24
Non-Patent Document 2: J. Biol. Chem. 278 (2003) 27329-27332
Non-Patent Document 3: Diabetes 43 (1994) 143-153